Ventricular fibrillation (VF) is a leading cause of death in the industrialized world. The only effective treatment for VF is electrical defibrillation. In te US alone, approximately 150,000 patients at high risk of VF receive implantable cardioverter defibrillators (ICDs) each year. The large shocks delivered by ICDs may lead to cardiac damage and anxiety in patients. Significant reductions in defibrillation shock energy may lead to reduced mortality and improved quality of life for ICD patients. The overall goal of this proposal is to develop a clinically relevant defibrillation strategy that significantly lowers the shock energy below the pain and damage thresholds of conventional defibrillation shocks. The main hypothesis of this proposal is that critically timed pacing-level pulses delivered directly to the Purkinje system will capture a critical mass of cardiac tissue and terminate VF. This work builds on recent understanding that the Purkinje system plays and active role in the maintenance of VF, a recent resurgence of work in low-energy defibrillation techniques, and the emergence of clinically available lead systems that directly interface the His-Purkinje system. The specific aims of this proposal are to: 1) demonstrate that there is an excitable gap in the His-Purkinje system in VF during which pacing pulses capture large regions of fibrillating tissue, 2) determine which low-energy defibrillation algorithm terminates VF with the least amount of energy, and 3) demonstrate the implementation of these techniques in a clinically relevant model that may be integrated into current ICD technology. Completion of these aims will lead to further understanding of the role and importance of the Purkinje system in cardiac arrhythmias. It will demonstrate that low energy defibrillation techniques which have only been demonstrated to be effective in small animal hearts and simulations are effective in larger hearts if the specialized conduction system is used to distribute pacing pulses throughout the working myocardium. The techniques will be developed and tested in normal and heart failure animal models. The end result of this project will be a clinically translatable technique and algorithm for terminating VF with pulse so small that damage and pain from defibrillation therapy with ICDs will be eliminated entirely.